Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial

• Published in: Nature medicine Vol. 27; no. 12; pp. 2192 - 2199
• Main Authors: Gotlib, Jason, Reiter, Andreas, Radia, Deepti H., Deininger, Michael W., George, Tracy I., Panse, Jens, Vannucchi, Alessandro M., Platzbecker, Uwe, Alvarez-Twose, Iván, Mital, Andrzej, Hermine, Olivier, Dybedal, Ingunn, Hexner, Elizabeth O., Hicks, Lisa K., Span, Lambert, Mesa, Ruben, Bose, Prithviraj, Pettit, Kristen M., Heaney, Mark L., Oh, Stephen T., Sen, Jayita, Lin, Hui-Min, Mar, Brenton G., DeAngelo, Daniel J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2021; Nature Publishing Group
• Subjects: 631/250/2504/223/1630; 631/67/1990/2331; 692/308/2779/109/1941; 692/699/67/1990/2331; Adult; Aged; Aged, 80 and over; Anemia; Biomedical and Life Sciences; Biomedicine; Bone marrow; Cancer; Cancer Research; Care and treatment; Cell survival; Clinical Trials, Phase II as Topic; Confidence intervals; Diagnosis; Drug dosages; Event history analysis; Female; Hematology; Hospitals; Humans; Infectious Diseases; Inhibitors; Kinases; Male; Mast cell disease; Mast cells; Mastocytosis; Mastocytosis, Systemic - drug therapy; Medicine; Metabolic Diseases; Methods; Middle Aged; Molecular Medicine; Mutation; Neurosciences; Neutropenia; Oncology; Patients; Population; Pyrazoles - adverse effects; Pyrazoles - therapeutic use; Pyrroles - adverse effects; Pyrroles - therapeutic use; Quality of life; Remission; Remission (Medicine); Response rates; Risk factors; Safety; Survival; Thrombocytopenia; Triazines - adverse effects; Triazines - therapeutic use; Tryptase; Tumors; Germany
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-021-01539-8

Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase 2 trial (no. NCT03580655 ) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200 mg in patients with AdvSM ( n  = 62). The primary endpoint was overall response rate (ORR). Secondary endpoints included mean baseline change in AdvSM–Symptom Assessment Form Total Symptom Score and quality of life, time to response, duration of response, progression-free survival, overall survival, changes in measures of disease burden and safety. The primary endpoint was successfully met ( P  = 1.6 × 10 -9 ), with an ORR of 75% (95% confidence interval 57–89) in 32 response-evaluable patients with AdvSM who had sufficient follow-up for response assessment, including 19% with complete remission with full or partial hematologic recovery. Reductions of ≥50% from baseline in serum tryptase (93%), bone marrow mast cells (88%) and KIT D816V variant allele fraction (60%) were observed. The most frequent grade ≥3 adverse events were neutropenia (24%), thrombocytopenia (16%) and anemia (16%). Avapritinib demonstrated a high rate of clinical, morphological and molecular responses and was generally well tolerated in patients with AdvSM. In a prespecified interim analysis of a pivotal phase 2 trial, avapritinib, a selective KIT inhibitor, elicited robust clinical and molecular responses, was generally well tolerated and led to improved patient-reported outcomes in patients with advanced systemic mastocytosis.